THE VALUE OF PREOPERATIVE PROGNOSTIC NUTRITIONAL INDEX IN GASTRIC CANCER AFTER CURATIVE RESECTION

ABSTRACT BACKGROUND: Predicting short- and long-term outcomes of oncological therapies is crucial for developing effective treatment strategies. Malnutrition and the host immune status significantly affect outcomes in major surgeries. AIMS: To assess the value of preoperative prognostic nutritional index (PNI) in predicting outcomes in gastric cancer patients. METHODS: A retrospective cohort analysis was conducted on patients undergoing curative-intent surgery for gastric adenocarcinoma between 2009 and 2020. PNI was calculated as follows: PNI=(10 x albumin [g/dL])+(0.005 x lymphocytes [nº/mm3]). The optimal cutoff value was determined by the receiver operating characteristic curve (PNI cutoff=52), and patients were grouped into low and high PNI. RESULTS: Of the 529 patients included, 315 (59.5%) were classified as a low-PNI group (PNI<52) and 214 (40.5%) as a high-PNI group (PNI≥52). Older age (p=0.050), male sex (p=0.003), American Society of Anesthesiologists score (ASA) III/IV (p=0.001), lower hemoglobin level (p<0.001), lower body mass index (p=0.001), higher neutrophil-lymphocyte ratio (p<0.001), D1 lymphadenectomy, advanced pT stage, pN+ and more advanced pTNM stage were related to low-PNI patient. Furthermore, 30-day (1.4 vs. 4.8%; p=0.036) and 90-day (3.3 vs. 10.5%; p=0.002) mortality rates were higher in low-PNI compared to high-PNI group. Disease-free and overall survival were worse in low-PNI patients compared to high-PNI (p<0.001 for both). ASA III/IV score, low-PNI, pT3/T4, and pN+ were independent risk factors for worse survival. CONCLUSIONS: Preoperative PNI can predict short- and long-term outcomes of patients with gastric cancer after curative gastrectomy. Low PNI is an independent factor related to worse disease-free and overall survival.


A QUEDA DA PRESSÃO PORTAL APÓS DESVASCULARIZAÇÃO ESOFAGOGÁSTRICA E ESPLENECTOMIA INFLUENCIA A VARIAÇÃO DO CALIBRE DAS VARIZES E AS TAXAS DE RESSANGRAMENTO NA ESQUISTOSSOMOSE NO SEGUIMENTO EM LONGO PRAZO?
Does the drop in portal pressure after esophagogastric devascularization and splenectomy variation of variceal calibers and the rebleeding rates in schistosomiasis in late follow-up?
Walter de Biase SILVA-NETO 1 , Claudemiro QUIRESE 1 , Eduardo Guimarães Horneaux de MOURA 2 , Fabricio Ferreira COELHO 3 , Paulo HERMAN 3 ABSTRACT -Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy.However, studies have shown varices recurrence especially after long-term follow-up.Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS.Methods: Thirty-six patients submitted to EGDS portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence.Results late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy.

Central Message
The preoperative prognostic nutritional index can predict short-and long-term outcomes of patients with gastric cancer after curative gastrectomy.staged according to the TNM staging system from the eighth edition of the American Joint Committee on Cancer manual 2 .

Data extraction
The following data were extracted: blood test results, computed tomography reports, age, sex, body mass index (BMI), the extent of lymphadenectomy, type of resection, tumor size, histological type, lymphatic invasion, venous invasion, perineural invasion, American Society of Anesthesiologists (ASA) preoperative risk score, and Charlson comorbidity index (CCI), without age and neoplasia in the score.
Follow-up was performed every three months in the first year and every six months after this period, with a clinical evaluation.Studies to detect relapse were performed based on the presence of symptoms.

Outcomes
Postoperative complications were classified using the Clavien-Dindo scale.Clavien-Dindo ≥ 3a were considered major complications 12 .We evaluated 30-and 90-day mortality rates after surgical resection.Overall survival (OS) and disease-free survival (DFS) were estimated based on the interval from surgery to death, recurrence, or the last contact.

Statistical analysis
The data were described as mean and standard deviation (SD) for quantitative variables and absolute and relative frequencies for qualitative variables.
The receiver operating characteristic (ROC) curve with area under the curve (AUC) was plotted to evaluate the ability of PNI to predict 90-day mortality.The optimal cutoff value was determined by the maximum Youden index, and patients were grouped into "low-PNI" and "high-PNI" groups.Pearson's chisquare (χ²) test, Student t-test, or the Mann-Whitney U test were used for comparisons.
The Kaplan-Meier curve was used to analyze survival, and the Log-rank test was used to compare the groups.Multivariate cyclooxygenase (Cox) proportional hazard analysis was performed to determine independent risk factors for survival.Only variables significant in univariate analysis (p<0.050) were selected for the multivariate analysis.
A significance level of 5% was considered, and the analyses were performed using the Statistical Package for Social Sciences (SPSS), v20.0 software (IBM Corp., 2016).
This study was approved by the local Ethics Committee, which waived the consent form (CAAE: 43247321.0.0000.0068).

RESULTS
Of the 1,330 surgeries performed, 529 patients met the inclusion criteria and were evaluated in this study.Figure 1 shows the flow diagram with the patients' selection.The mean age was 62.8 years (range 22-94), and 59.5% were male.Subtotal gastrectomy and D2 lymphadenectomy were performed in 64.1% and 82.4% of patients, respectively.Stage III was the most common (43.1%), and 55.5% of patients had lymph node metastasis (pN+).
Thus, based on the cutoff value determined by the ROC curve, 315 (59.5%) patients were classified as a low-PNI group (PNI<52); and 214 (40.5%) as a high-PNI group (PNI>52).The clinical and surgical characteristics of both groups are presented in Table 1.

INTRODUCTION
G astric cancer (GC) is a significant health concern worldwide, characterized by its low survival rates due to its frequent diagnosis at advanced stages 17,31 .Surgery remains the primary curative option for most patients 16 .However, gastrectomy is associated with a significant risk of postoperative complications and mortality.Over 20% of patients experienced substantial postoperative morbidity, and the 30-day mortality rate was around 4% 24 .
The risk of surgical complications is especially relevant in cancer due to preoperative nutritional deterioration commonly found in GC patients.The obstructive nature of gastric neoplasms leads patients undergoing gastric resection to experience prolonged periods of reduced caloric and protein intake before surgery 3 .Furthermore, cancer stimulates the production of inflammatory interleukins, as indicated by increased serum inflammatory markers in cancer patients.This inflammatory condition contributes to a worse prognosis for the patient and an increased risk of postoperative complications 37,38,41,42 .In this setting, having a straightforward preoperative strategy to stratify patients at risk for poor postoperative outcomes is crucial for improving patient selection for gastric resection.A clear preoperative strategy can help identify patients likely to benefit most from surgery and those requiring additional support or interventions before the procedure.By identifying high-risk patients early on, healthcare providers can implement pre-habilitation programs to optimize patients' physical and nutritional status, potentially reducing postoperative complications and improving outcomes 34 .
Considering the close relationship between malnutrition and host's immune status and postoperative outcomes, preoperative markers of nutrition and systemic inflammation are crucial for stratifying risk in GC patients.The prognostic nutritional index (PNI) is a straightforward marker of nutrition status and systemic inflammation.This index is based on serological routine tests, calculated as PNI=(10 × albumin [g/dL])+(0.005× lymphocytes [nº/mm 3 ]).Thus, this study aimed to evaluate the significance of preoperative PNI as a predictor of short-and long-term outcomes in GC patients.

Study design
A retrospective cohort was conducted on patients submitted to gastrectomy in a single cancer institute.An experienced surgical oncology team performed all surgeries.The surgical technique was performed according to the Japanese Gastric Cancer Association guidelines 16 and the Brazilian Gastric Cancer consensus 4 .

Eligibility
Patients with GC who underwent potentially curative gastrectomy between 2009 and 2020 were included.Only patients with histologically proven gastric adenocarcinoma and D1 or D2 lymphadenectomy were selected.Exclusion criteria comprised metastatic disease, gastric remnant tumors, infection, emergency surgery, or incomplete medical records.

Preoperative workup
Data were collected prospectively from a database.All patients were submitted to clinical and anesthesia preoperative evaluation.Patients underwent blood tests, endoscopy, and computed tomography (chest and abdominal) up to one month before surgery.Preoperative PNI was defined as PNI= (     Older age (p=0.050),male sex (p=0.003),ASA III/IV (p=0.001),lower hemoglobin level (p<0.001),lower BMI (p=0.001),higher neutrophil-lymphocyte ratio (p<0.001) and D1 lymphadenectomy were more common in the low-PNI group.
Regarding pathological characteristics (Table 2), the low-PNI group had larger tumors (p<0.001) and a higher rate of venous (p<0.001) and perineural invasion (p=0.037)compared to the high-PNI group.Furthermore, patients with low PNI were associated with more advanced pT stage (p<0.001),presence of lymph node metastasis (p=0.033), and more advanced pTNM (p=0.004).

Survival analysis
The median follow-up was 36.8 months, 119 patients had recurrence, and 194 died during the follow-up.The estimated 5-year OS for the entire cohort was 57.3%.Low-PNI patients had a worse DFS and OS compared to the high-PNI group (estimated 5-year DFS: 71.2 vs 45.3%, p<0.001; estimated 5-year OS: 72.9 vs 46.4%, p<0.001) (Figure 3).
In multivariate analysis, ASA III/IV score, low PNI, total gastrectomy, advanced tumor stage (pT3/T4), and presence of positive lymph nodes (pN+) were independent risk factors for worse DFS and OS in GC patients.Table 3 shows the univariate and multivariate analyses.

DISCUSSION
Inflammation and malnutrition are critical factors in the prognosis of GC.In this setting, PNI is a valuable marker, providing insights into the impact of the host's immune system status  and malnutrition on surgical outcomes.Our findings suggest that preoperative lymphocyte reduction, alongside a protein deficiency, is associated with a higher risk for postoperative mortality and decreased survival.This study showed that low PNI values are associated with worse histopathological prognostic variables, such as venous and perineural invasion, pN, and pT.These results indicate that PNI might have a significant role in cancer progression and dissemination, and consequently, PNI can depict the tumor's aggressiveness.These biological features of bad prognosis eventually promote poor long-term survival rates.Other studies also showed that PNI might have a significant impact on survival rates in endometrial, ovarian, and esophageal cancer 18,27,46 .
In addition, our study showed that PNI was associated with age, ASA classification, extent of lymphadenectomy, and postoperative mortality, which implies that PNI also reveals patients' vulnerabilities and overall clinical status.Consequently, PNI presents a global picture of the patient and the tumor and can be a valuable tool for GC patients' risk stratification.In our center, gastrectomy with D1 dissection is generally performed in elderly or frail patients with lowperformance status and comorbidities, which is what was observed in the low-PNI group 30,36 .
Patient stratification is crucial in planning preoperative strategies for individuals undergoing surgery.By identifying patients at risk of poor outcomes, healthcare providers can implement tailored interventions 32 .Prehabilitation programs, which include nutritional support, exercise, and psychological interventions, can help improve at-risk patients' physical and mental resilience before surgery 15 .Nutritional support, such as oral supplements or enteral nutrition, can help correct nutritional deficiencies and improve overall health status 43 .Stratifying patients allows for personalized care plans that address specific needs, ultimately reducing the risk of complications, postoperative mortality, and longer survival rates 9 .
The tumor-associated inflammatory response reflects the host's immune status and antitumor immune response 14 .Inflammation plays a significant role in cancer development and progression, affecting tumor initiation, promotion, and metastasis 10,25 .Cancer cells release growth factors and inflammatory mediators that stimulate the production of peripheral leucocytes, producing factors that disrupt the tumor stroma, facilitating invasion and metastasis 1,22 .Tumors attract inflammatory cells, including macrophages and lymphocytes, which produce cytokines and chemokines 40 .Chronic inflammation creates a tumor-promoting microenvironment by releasing inflammatory mediators, growth factors, and cytokines, stimulating cell proliferation, angiogenesis, and resistance to cell death.Inflammation also suppresses the immune response against tumors, allowing cancer cells to evade immune surveillance 8 .Lymphocytes play a crucial role in eliminating neoplastic cells, and lymphopenia weakens the antitumor immune response, increasing the probability of tumor dissemination 8,25 .
As a result, persistent inflammation is associated with a poorer prognosis in various types of cancer, including gastric cancer.Inflammatory markers, such as the neutrophil-tolymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels, have been identified as prognostic indicators in numerous cancer types 6,21,26,33,44,45 .
High levels of these markers are often associated with more aggressive tumor behavior, higher rates of recurrence, and poorer survival outcomes, as seen in previous studies with GC patients undergoing jejunostomy, stage IV GC, and patients with multivisceral resections 11,28,29 .Previous studies have highlighted the relevance of systemic markers of systemic inflammation markers on gastric and esophagogastric cancer prognosis.Szor et al. 38 evaluated the role of NLR, a systemic inflammation biomarker, on gastric cancer prognosis.The authors found that NLR was associated with lower survival rates, higher depth of tumor invasion, and positive nodal involvement.Tustumi et al. 41 studied esophageal cancer patients undergoing neoadjuvant chemoradiotherapy followed by esophagectomy.They found that lymphocytes decreased during neoadjuvant therapy and predicted severe postoperative complications.In addition, a high NLR was associated with a higher risk for recurrence and low survival rates.
Albumin is commonly used as a nutritional assessment marker before surgery due to its widespread availability and relatively low cost.It serves as an indicator of nutritional status, reflecting long-term dietary intake and protein synthesis 35 .Low albumin levels have been linked to increased morbidity and mortality in surgical patients, making it a valuable prognostic indicator.In addition, albumin also plays a role in depicting patients' systemic inflammation 13 .Albumin levels can decrease during inflammatory states due to increased capillary permeability and redistribution.Despite its convenience, albumin has limitations.Its levels can be affected by factors beyond nutrition or inflammation, such as liver disease and hydration status, reducing specificity 7 .Consequently, in addition to albumin levels, a comprehensive nutritional evaluation should include a precise clinical assessment and measures of sarcopenia 19 .Clinical evaluation involves assessing factors such as weight loss, dietary intake, and physical function, which can provide valuable insights into a patient's nutritional status.Measures of sarcopenia, such as muscle mass and strength assessments, can help identify patients at risk of poor surgical outcomes and guide preoperative interventions 5 .Combining these assessments with traditional nutritional markers like albumin levels can provide a more holistic understanding of a patient's nutritional status and help tailor preoperative strategies to improve outcomes.
Malnutrition is a significant risk factor for adverse outcomes in patients undergoing cancer resection surgeries, including an increased risk of mortality 20 .Malnutrition weakens the immune system, impairs wound healing, and reduces the body's ability to withstand the stress of surgery, leading to an increased risk of postoperative complications.Malnourished patients are more likely to experience surgical site infections, delayed wound healing, and prolonged hospital stays, all of which contribute to an increased risk of mortality.Additionally, malnutrition can exacerbate the catabolic state induced by surgery, leading to further muscle wasting and functional decline 23 .
The current study has limitations.The dynamic nature of blood cellular components and albumin levels, which may vary daily in the same patient, and the influence of factors other than systemic inflammation and malnutrition should be considered.Besides, numerous approaches exist for determining optimal cutpoints for PNI.The choice of cutpoint in continuous variables can influence p-values, leading to the acceptance or rejection of null hypotheses.We determined the cutpoint based on the Youden index in ROC curves for the outcome "90-day mortality".This choice has some drawbacks since time-toevent outcomes, such as OS and DFS, might not be precisely discretized according to the Youden index 39 .
Larger, controlled prospective studies are warranted to validate the predictive value of these inflammatory markers in GC prognosis.Indeed, future research is necessary beyond validating inflammatory markers in GC prognosis.Developing nomograms and prognostic calculators could significantly enhance the ability to determine the best treatment strategy for patients with GC.These tools could integrate various clinical, pathological, and inflammatory markers and nutritional status indicators to assess the patient's condition comprehensively.Additionally, future trials should incorporate prehabilitation and preoperative nutritional support according to risk stratification estimation, optimizing patient outcomes by addressing malnutrition and enhancing physiological reserves before surgery.

CONCLUSIONS
Preoperative PNI can predict short-and long-term outcomes of patients with GC after curative gastrectomy, and low PNI is an independent factor related to worse DFS and OS.Also, low-PNI patients have poor clinical conditions, advanced pathological stage, and high postoperative mortality compared to those with high-PNI.These findings underscore the importance of considering inflammatory markers and nutritional status in managing GC patients, with the potential to improve risk stratification and treatment outcomes.

Figure 3 -
Figure 3 -Disease-free survival and overall survival according to prognostic nutritional index groups.

Figure 2 -
Figure 2 -A receiver operating characteristic curve was performed to predict 90-day mortality according to the prognostic nutritional index value.

Figure 3 -
Figure 3 -Disease-free survival and overall survival according to prognostic nutritional index groups.

Table 1 -
Clinical and surgical characteristics according to the prognostic nutritional index.

Table 2 -
Pathological characteristics and postoperative outcomes according to the prognostic nutritional index.

Table 3 -
Univariate and multivariate analysis for disease-free survival and overall survival.